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MRI Shows Small Vessel Degeneration Is Bidirectional Between Gray and White Matter

Key findings

  • In this study, 1,062 MRIs of cognitively normal adults with cerebral small vessel disease (SVD) were analyzed to explore changes in gray matter (GM) and white matter (WM)
  • GM and WM lesions showed significant connectivity across the brain, occurring in four main "modules" (stable patterns of how regions of GM interacted with regions of WM)
  • This strict network organization was critical to adequate cognitive performance, particularly for executive function
  • Degeneration in SVD was bidirectional: Some primary GM lesions caused secondary WM degeneration in vascular-vulnerable areas of the brain, whereas some primary WM lesions led to GM degeneration in cortical projecting areas
  • The androgen receptor gene seemed to play a key role in GM-to-WM degeneration in SVD

White matter (WM) hyperintensity on MRI is one of the best-characterized features of cerebral small vessel disease (SVD), and it correlates with clinical findings in older adults. Recently, though, it's been hypothesized that WM damage could lead to neurodegeneration in distant areas of the brain, affecting both WM and gray matter (GM) remotely and impairing the network functionality of the whole brain.

Raquel Gutiérrez- Zúñiga, MD, PhD, formerly a research fellow in the Gordon Center for Medical Imaging at Massachusetts General Hospital, Jorge Sepulcre, MD, PhD, a faculty member in the Center, and colleagues have gone one step further in understanding this complex relationship. In Neurobiology of Disease, they show the degeneration in SVD is bidirectional between GM and WM lesions, and they identify a gene that seems to be key in conferring vulnerability to SVD.


The researchers examined MRIs from individuals who had imaging signs of SVD but were cognitively normal and otherwise neurologically normal. Two types of analyses were conducted:

  • Cross-sectional analyses of structural connectivity between GM and WM—336 MRIs from the third of the Open Access Series of Imaging Studies (OASIS-3), and 526 MRIs from the Cambridge Center for Aging and Neuroscience
  • A longitudinal analysis of connectivity—200 MRIs from OASIS-3, not used in the cross-sectional analyses, contributed by participants who completed a battery of cognitive tests and had at least one follow-up MRI an average of 4.5 years later

Connectivity Interactions

The researchers observed GM and WM lesions showed significant connectivity across the brain. Alterations in GM and WM did not occur in isolation but rather in four main "modules" (patterns of how regions of GM interacted with regions of WM).

Moreover, the two modules that reflected GM–WM connections in the frontal and temporal lobes related to cognitive performance, especially on tests of executive function. Impairment of executive function is the main feature of vascular cognitive decline.

Longitudinal Analysis

The longitudinal analysis found certain regions in the brain were particularly vulnerable to GM-to-WM or WM-to-GM degeneration. Some primary GM lesions caused secondary WM degeneration in vascular border zone areas, whereas some primary WM lesions led to GM degeneration in projecting areas of the frontal lobe.

Genetic Factors

The researchers also investigated similarities between cortical maps and genetic profiles using the Allen Human Brain Atlas. They found relationships between GM-to-WM degeneration and expression levels of 683 genes. Five of those genes (AR, CNN1, CSF3, ITGA8 and MYLK2) have been linked previously to SVD.

In this study, AR, the androgen receptor gene, displayed a central role in SVD according to an independent dataset of gene–gene network interactions.

The WM-to-GM cortical map was associated with 476 genes, of which IL1-b, IL-6, and TRIBE3 seemed potentially relevant to SVD pathology. However, those results were not as conclusive.

Looking Ahead

These results suggest new directions for studying the pathophysiology of SVD. The finding that AR has a key role in brain lesion vulnerability and network breakdown in this disease may have therapeutic implications.

Learn more about the Gordon Center for Medical Imaging

Learn more about Radiology Research at Mass General


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